[Technical Field]
[0001] The present disclosure relates to the field of pharmaceuticals, healthcare, biology,
biotechnology, etc. The present disclosure particularly relates to application of
a Vi/Vc zone inhibitor and/or improvement in a dry eye symptom.
[Background Art]
[0002] It is estimated that there are at least about 8 million dry eye patients in Japan,
or about 22 million patients including potential patients who use commercially available
eye drops without visiting a hospital, and 1 billion or more worldwide. It is well
known that modern society provides more opportunities for gazing at screens from using
televisions, computers, mobile terminals, etc., so that the number of blinking has
decreased, and the air has dried with use of air conditioners, etc., resulting in
increased evaporation of lachrymal fluid to induce dry eye. Refractive surgeries and
use of contact lens use also result in dry eye. Examples of symptoms associated with
dry eye include ocular discomfort, dryness, burning sensation, irritation, and the
like on the ocular surface. More severe forms of dry eye include dry eye induced by
destruction of a lachrymal gland due to a disease such as an autoimmune disease such
as Sjogren's syndrome and Stevens-Johnson syndrome (Non Patent Literature 1).
[0003] The effect of treatments for dry eye is evaluated from external observation or evaluation
(objective finding) and a subjective viewpoint of a patient such as ocular discomfort
or foreign body sensation (subjective symptom). Objective finding uses the amount
of lachrymal fluid and observation of a site of disorder on the keratoconjunctive
epithelium as endpoints. While each of sodium hyaluronate, diquafosol sodium, and
Rebamipide sold in Japan, and ciclosporin sold in the US have been approved as a prescription
eye drop for dry eye, few are approved as an eye drop satisfying improvement in subjective
symptoms as a primary endpoint in addition to improvement in objective finding.
[Citation List]
[Non Patent Literature]
[Summary of Invention]
[Solution to Problem]
[0005] The present disclosure relates to a novel dry eye therapeutic agent using a heterocyclidene
acetamide derivative (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide,
use thereof, a method for treatment or prevention, and the like. The present disclosure
also relates to a Vi/Vc zone inhibitor using said compound, use thereof, a method
for treatment or prevention, and the like.
[0006] Another aspect of the present disclosure relates to a composition for the treatment
and/or prevention of dry eye using a Vi/Vc zone inhibitor, use thereof, a method for
treatment or prevention, and the like.
[0007] The treatment of dry eye can be improvement of a subjective symptom of dry eye. Dry
eye treatment can also include improvement of an objective symptom of dry eye. In
the present disclosure, dry eye treatment can include improvement of both a subjective
symptom and an objective symptom of dry eye.
[0008] Examples of the embodiments of the present disclosure include the following.
(Item 1)
[0009] A composition for use in treating dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 2)
[0010] The composition of the preceding item for use in improving a subjective symptom of
dry eye.
(Item 2A)
[0011] The composition of the preceding item, wherein the dry eye is accompanied by a subjective
symptom.
(Item 3)
[0012] The composition of any of the preceding items for suppressing ocular discomfort associated
with dryness.
(Item 3A)
[0013] The composition of any of the preceding items, wherein the dry eye is accompanied
by ocular discomfort associated with dryness.
(Item 4)
[0014] The composition of any of the preceding items for use in improving an objective symptom
of dry eye.
(Item 4A)
[0015] The composition of any of the preceding items, wherein the dry eye is accompanied
by an objective symptom.
(Item 5)
[0016] The composition of any of the preceding items for use in improving a subjective symptom
and an objective symptom of dry eye.
(Item 5A)
[0017] The composition of any of the preceding items, wherein the dry eye is accompanied
by a subjective symptom and an objective symptom.
(Item 6)
[0018] The composition of any of the preceding items, wherein a concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 1.0
w/v %.
(Item 7)
[0019] The composition of any of the preceding items, which is an eye drop.
(Item 8)
[0020] The composition of any of the preceding items, which is a suspension.
(Item 9)
[0021] The composition of any of the preceding items, wherein the dry eye is aqueous deficient
dry eye.
(Item 10)
[0022] The composition of any of the preceding items, characterized in that the composition
is administered to a patient who has a subjective symptom of ocular discomfort and
has been diagnosed as having dry eye.
(Item 11)
[0023] A composition for use in suppressing ocular discomfort associated with dryness, comprising
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 12)
[0024] A composition for use in improving a subjective symptom of dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 13)
[0025] A composition for use in improving an objective symptom of dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 14)
[0026] A composition for use in treating a corneal epithelial disorder, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 15)
[0027] A suspension for use in suppressing ocular discomfort associated with dryness, comprising
about 0.3 to about 1.0 w/v % of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 16)
[0028] A Vi/Vc zone inhibitor comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item 17)
[0029] A composition for use in treating dry eye, comprising a Vi/Vc zone inhibitor.
(Item 18)
[0030] The composition of the preceding item for use in improving a subjective symptom of
dry eye.
(Item 19)
[0031] The composition of any of the preceding items for use in suppressing ocular discomfort
associated with dryness.
(Item 20)
[0032] The composition of any of the preceding items for use in improving an objective symptom
of dry eye.
(Item 21)
[0033] The composition of any of the preceding items, which is an eye drop.
(Item 22)
[0034] The composition of any of the preceding items, which is a suspension.
(Item 23)
[0035] The composition of any of the preceding items, wherein the dry eye is aqueous deficient
dry eye.
(Item 24)
[0036] The composition of any of the preceding items, characterized in that the composition
is administered to a patient who has a subjective symptom of ocular discomfort and
has been diagnosed as having dry eye.
(Item 25)
[0037] A composition for use in suppressing ocular discomfort associated with dryness, comprising
a Vi/Vc zone inhibitor.
(Item 26)
[0038] A composition for use in improving a subjective symptom of dry eye, comprising a
Vi/Vc zone inhibitor.
(Item 27)
[0039] The composition of any of the preceding items, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[0040] Examples of other embodiments of the present disclosure include the following.
(Item A1)
[0041] A method of use in treating dry eye in a patient in need thereof, comprising administering
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A2)
[0042] The method of the preceding item for use in improving a subjective symptom of dry
eye.
(Item A2A)
[0043] The method of the preceding item, wherein the dry eye is accompanied by a subjective
symptom.
(Item A3)
[0044] The method of any of the preceding items for suppressing ocular discomfort associated
with dryness.
(Item A3A)
[0045] The method of any of the preceding items, wherein the dry eye is accompanied by ocular
discomfort associated with dryness.
(Item A4)
[0046] The method of any of the preceding items for use in improving an objective symptom
of dry eye.
(Item A4A)
[0047] The method of any of the preceding items, wherein the dry eye is accompanied by an
objective symptom.
(Item A5)
[0048] The method of any of the preceding items for use in improving a subjective symptom
and an objective symptom of dry eye.
(Item A5A)
[0049] The method of any of the preceding items, wherein the dry eye is accompanied by a
subjective symptom and an objective symptom.
(Item A6)
[0050] The method of any of the preceding items, wherein the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof is administered at a concentration
of about 0.1 to about 1.0 w/v %.
(Item A7)
[0051] The method of any of the preceding items, wherein the compound is administered as
an eye drop.
(Item A8)
[0052] The method of any of the preceding items, wherein the compound is administered as
a suspension.
(Item A9)
[0053] The method of any of the preceding items, wherein the dry eye is aqueous deficient
dry eye.
(Item A10)
[0054] The method of any of the preceding items, characterized in that the composition is
administered to a patient who has a subjective symptom of ocular discomfort and has
been diagnosed as having dry eye.
(Item A11)
[0055] A method of use in suppressing ocular discomfort associated with dryness in a patient
in need thereof, comprising administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A12)
[0056] A method of use in improving a subjective symptom of dry eye in a patient in need
thereof, comprising administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A13)
[0057] A method of use in improving an objective symptom of dry eye in a patient in need
thereof, comprising administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A14)
[0058] A method of use in treating a corneal epithelial disorder in a patient in need thereof,
comprising administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A15)
[0059] A method for use in suppressing ocular discomfort associated with dryness in a patient
in need thereof, comprising administering a suspension comprising about 0.3 to about
1.0 w/v % of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof to the patient.
(Item A16)
[0060] A method of use in inhibiting a Vi/Vc zone comprising administering (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
(Item A17)
[0061] A method of use in treating dry eye in a patient in need thereof, comprising administering
a Vi/Vc zone inhibitor.
(Item A18)
[0062] The method of the preceding item for use in improving a subjective symptom of dry
eye.
(Item A19)
[0063] The method of any of the preceding items for use in suppressing ocular discomfort
associated with dryness.
(Item A20)
[0064] The method of any of the preceding items for use in improving an objective symptom
of dry eye.
(Item A21)
[0065] The method of any of the preceding items for use in administering the Vi/Vc zone
inhibitor as an eye drop.
(Item A22)
[0066] The method of any of the preceding items for use in administering the Vi/Vc zone
inhibitor as a suspension.
(Item A23)
[0067] The method of any of the preceding items, wherein the dry eye is aqueous deficient
dry eye.
(Item A24)
[0068] The method of any of the preceding items, wherein the Vi/Vc zone inhibitor is administered
to a patient who has a subjective symptom of ocular discomfort and has been diagnosed
as having dry eye.
(Item A25)
[0069] A method of use in suppressing ocular discomfort associated with dryness in a patient
in need thereof, comprising administering a Vi/Vc zone inhibitor to the patient.
(Item A26)
[0070] A method of use in improving a subjective symptom of dry eye in a patient in need
thereof, comprising administering a Vi/Vc zone inhibitor to the patient.
(Item A27)
[0071] The method of any of the preceding items, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[0072] Examples of other embodiments of the present disclosure include the following.
(Item B1)
[0073] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in treating dry eye.
(Item B2)
[0074] The compound for use of the preceding item for improving a subjective symptom of
dry eye.
(Item B2A)
[0075] The compound for use of the preceding item, wherein the dry eye is accompanied by
a subjective symptom.
(Item B3)
[0076] The compound for use of any of the preceding items for suppressing ocular discomfort
associated with dryness.
(Item B3A)
[0077] The compound for use of any of the preceding items, wherein the dry eye is accompanied
by ocular discomfort associated with dryness.
(Item B4)
[0078] The compound for use of any of the preceding items for improving an objective symptom
of dry eye.
(Item B4A)
[0079] The compound for use of any of the preceding items, wherein the dry eye is accompanied
by an objective symptom.
(Item B5)
[0080] The compound for use of any of the preceding items for improving a subjective symptom
and an objective symptom of dry eye.
(Item B5A)
[0081] The compound for use of any of the preceding items, wherein the dry eye is accompanied
by a subjective symptom and an objective symptom.
(Item B6)
[0082] The compound for use of any of the preceding items, wherein a concentration of the
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 1.0
w/v %.
(Item B7)
[0083] The compound for use of any of the preceding items, which is contained in an eye
drop.
(Item B8)
[0084] The compound for use of any of the preceding items, which is contained in a suspension.
(Item B9)
[0085] The compound for use of any of the preceding items, wherein the dry eye is aqueous
deficient dry eye.
(Item B10)
[0086] The compound for use of any of the preceding items, wherein the compound is administered
to a patient who has a subjective symptom of ocular discomfort and has been diagnosed
as having dry eye.
(Item B11)
[0087] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in suppressing ocular
discomfort associated with dryness.
(Item B12)
[0088] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in improving a subjective
symptom of dry eye.
(Item B13)
[0089] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in improving an objective
symptom of dry eye.
(Item B14)
[0090] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in treating a corneal
epithelial disorder.
(Item B15)
[0091] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for suppressing ocular discomfort
associated with dryness, wherein the compound is contained at about 0.3 to about 1.0
w/v % in a composition that is a suspension .
(Item B16)
[0092] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof for use in blocking a Vi/Vc
zone.
(Item B17)
[0093] A Vi/Vc zone inhibitor for use in treating dry eye.
(Item B18)
[0094] The Vi/Vc zone inhibitor for use of the preceding item for improving a subjective
symptom of dry eye.
(Item B19)
[0095] The Vi/Vc zone inhibitor for use of any of the preceding items for suppressing ocular
discomfort associated with dryness.
(Item B20)
[0096] The Vi/Vc zone inhibitor for use of any of the preceding items for improving an objective
symptom of dry eye.
(Item B21)
[0097] The Vi/Vc zone inhibitor for use of any of the preceding items, which is an eye drop.
(Item B22)
[0098] The Vi/Vc zone inhibitor for use of any of the preceding items, which is a suspension.
(Item B23)
[0099] The Vi/Vc zone inhibitor for use of any of the preceding items, wherein the dry eye
is aqueous deficient dry eye.
(Item B24)
[0100] The Vi/Vc zone inhibitor for use of any of the preceding items, wherein the inhibitor
is administered to a patient who has a subjective symptom of ocular discomfort and
has been diagnosed as having dry eye.
(Item B25)
[0101] A Vi/Vc zone inhibitor for use in suppressing ocular discomfort associated with dryness.
(Item B26)
[0102] A Vi/Vc zone inhibitor for use in improving a subjective symptom of dry eye.
(Item B27)
[0103] The compound or Vi/Vc zone inhibitor for use of any of the preceding items, wherein
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[0104] Examples of other embodiments of the present disclosure include the following.
(Item C1)
[0105] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in treating dry eye.
(Item C2)
[0106] The use of the preceding item, wherein the medicament is for use in improving a subjective
symptom of dry eye.
(Item C2A)
[0107] The use of the preceding item, wherein the dry eye is accompanied by a subjective
symptom.
(Item C3)
[0108] The use of any of the preceding items, wherein the medicament is for use in suppressing
ocular discomfort associated with dryness.
(Item C3A)
[0109] The use of any of the preceding items, wherein the dry eye is accompanied by ocular
discomfort associated with dryness.
(Item C4)
[0110] The use of any of the preceding items, wherein the medicament is for use in improving
an objective symptom of dry eye.
(Item C4A)
[0111] The use of any of the preceding items, wherein the dry eye is accompanied by an objective
symptom.
(Item C5)
[0112] The use of any of the preceding items, wherein the medicament is for use in improving
a subjective symptom and an objective symptom of dry eye.
(Item C5A)
[0113] The use of any of the preceding items, wherein the dry eye is accompanied by a subjective
symptom and an objective symptom.
(Item C6)
[0114] The use of any of the preceding items, wherein a concentration of the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the medicament is about
0.1 to about 1.0 w/v %.
(Item C7)
[0115] The use of any of the preceding items, wherein the medicament is an eye drop.
(Item C8)
[0116] The use of any of the preceding items, wherein the medicament is a suspension.
(Item C9)
[0117] The use of any of the preceding items, wherein the dry eye is aqueous deficient dry
eye.
(Item C10)
[0118] The use of any of the preceding items, characterized in that the medicament is administered
to a patient who has a subjective symptom of ocular discomfort and has been diagnosed
as having dry eye.
(Item C11)
[0119] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in suppressing ocular discomfort associated with dryness.
(Item C12)
[0120] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in improving a subjective symptom of dry eye.
(Item C13)
[0121] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in improving an objective symptom of dry eye.
(Item C14)
[0122] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in treating a corneal epithelial disorder.
(Item C15)
[0123] Use of a suspension comprising about 0.3 to about 1.0 w/v % of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in suppressing ocular discomfort associated with dryness.
(Item C16)
[0124] Use of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament
for use in inhibiting a Vi/Vc zone.
(Item C17)
[0125] Use of a Vi/Vc zone inhibitor in the manufacture of a medicament for use in treating
dry eye.
(Item C18)
[0126] The use of the preceding item, wherein the medicament is foruse in improving a subjective
symptom of dry eye.
(Item C19)
[0127] The use of any of the preceding items, wherein the medicament is for use in suppressing
ocular discomfort associated with dryness.
(Item C20)
[0128] The use of any of the preceding items, wherein the medicament is for use in improving
an objective symptom of dry eye.
(Item C21)
[0129] The use of any of the preceding items, wherein the medicament is an eye drop.
(Item C22)
[0130] The use of any of the preceding items, wherein the medicament is a suspension.
(Item C23)
[0131] The use of any of the preceding items, wherein the dry eye is aqueous deficient dry
eye.
(Item C24)
[0132] The use of any of the preceding items, characterized in that the medicament is administered
to a patient who has a subjective symptom of ocular discomfort and has been diagnosed
as having dry eye.
(Item C25)
[0133] Use of a Vi/Vc zone inhibitor in the manufacture of a medicament for use in suppressing
ocular discomfort associated with dryness.
(Item C26)
[0134] Use of a Vi/Vc zone inhibitor in the manufacture of a medicament for use in improving
a subjective symptom of dry eye.
(Item C27)
[0135] The use of any of the preceding items, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is preferably (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[Advantageous Effects of Invention]
[0136] The present disclosure provides novel means for preventing and/or treating dry eye,
and can preferably materialize improvement of a subjective symptom and more preferably
improvement of both a subjective symptom and an objective symptom. The composition
or method of the present disclosure can provide treatment with an immediate effect
on dry eye.
[Brief Description of Drawings]
[0137]
[Figure 1] Figure 1 is a diagram showing changes in the superficial punctate keratitis (SPK) score in
a rat after drug administration. The 0.3% w/v compound (1) suspension eye drop significantly
reduced the SPK score after 7 days from administration (after 15 days post-surgery)
in comparison to a Vehicle eye drop, and the effect thereof was sustained after 14
days from administration (after 22 days post-surgery). A rat scopolamine induced dry
eye model is denoted as SCOP, and a model loaded with saline instead of scopolamine
is denoted as Saline.
[Figure 2] Figure 2 is a diagram showing the number of blinks within 5 minutes, after 0.5 hours from
administration of a Vehicle eye drop or a 0.1 w/v %, 0.3 w/v %, or 1.0 w/v % compound
(1) suspension eye drop. Compound (1) reduced the number of blinks in the range from
0.1 w/v % to 1.0 w/v %, and a significant effect was observed at 0.3 w/v % and 1.0
w/v %.
[Figure 3] Figure 3 is a diagram showing the number of blinks within 5 minutes, after 0.5 hours from
a single administration of a vehicle eye drop or after 0.5, 4, or 8 hours from a single
administration of 1.0 w/v % compound (1) suspension eye drop. The number of blinks
after 0.5, 4, and 8 hours from administration of a 1.0 w/v % compound (1) suspension
eye drop can be reduced to a lower number than the number of blinks after 0.5 hours
from administration of a vehicle eye drop. In particular, the number of blinks after
0.5 and 4 hours was significantly reduced.
[Figure 4] Figure 4 is a diagram showing changes in the SPK score in a rat after 8 days of repeated administration
of a vehicleeye drop or 1.0 w/v % compound (1) suspension eye drop. The 1.0 w/v %
compound (1) suspension eye drop reduced the SPK score after 7 days from administration
(after 15 days post-surgery) in comparison to the vehicle eye drop.
[Figure 5] Figure 5 is a diagram showing the number of blinks within 5 minutes in a rat after 8 days
of repeated administration of a vehicle eye drop or 1.0 w/v % compound (1) suspension
eye drop. The 1.0 w/v % compound (1) suspension eye drop reduced the number of blinks
in comparison to the vehicle eye drop.
[Description of Embodiments]
[0138] Hereinafter, the present disclosure is described. Throughout the entire specification,
a singular expression should be understood as encompassing the concept thereof in
the plural form, unless specifically noted otherwise. Thus, singular articles (e.g.,
"a", "an", "the", and the like in the case of English) should also be understood as
encompassing the concept thereof in the plural form, unless specifically noted otherwise.
The terms used herein should also be understood as being used in the meaning that
is commonly used in the art, unless specifically noted otherwise. Thus, unless defined
otherwise, all terminologies and scientific technical terms that are used herein have
the same meaning as the general understanding of those skilled in the art to which
the present disclosure pertains. In case of a contradiction, the present specification
(including the definitions) takes precedence.
(Definitions)
[0139] As used herein, "about" refers to a range of ± 10% from the numerical value that
is described subsequent to "about", unless noted otherwise.
[0140] As used herein, "subject" refers to the target of administration (implantation) of
a drug or method for the treatment and prevention of the present disclosure. Examples
of subjects include mammals (e.g., humans, mice, rats, hamsters, rabbits, cats, dogs,
cows, horses, sheep, monkeys, etc.), but primates are preferable and humans are particularly
preferable.
[0141] As used herein, "or" is used when "at least one or more" of the listed matters in
the sentence can be employed. When explicitly described herein as "within the range"
of "two values", the range also includes the two values themselves.
[0142] As used herein, "treatment (therapy)" refers to healing or improvement of a disease
or a symptom, or suppression or alleviation of a symptom. "Treating dry eye" encompasses
treatment of an objective symptom or subjective symptom.
[0143] As used herein, "prevention" (prophylaxis) refers to the prevention of expression
of a disease or a symptom in advance. This concept also encompasses delaying the expression
of a disease or symptom and minimizing the expression of a disease or symptom by treatment
prior to onset or the like.
[0144] As used herein, "pharmaceutically acceptable salt" refers to an inorganic or organic
acid addition salt of the compound of the present disclosure that is relatively nontoxic.
These salts can be prepared by reacting a compound which is purified temporarily between
the final isolation and purification of the compound or in a free base form separately
with a suitable organic or inorganic salt, and isolating a salt formed in this manner.
[0145] As used herein, "solvate" refers to a solvate of the compound of the present disclosure
or a pharmaceutically acceptable salt thereof, encompassing, for example, a solvate
of an organic solvent (e.g., alcohol (ethanol or the like)-ate), hydrate, and the
like. When forming a hydrate, this can be coordinated with any number of water molecules.
Examples of hydrates include monohydrates, dihydrates, and the like.
[0146] As used herein, "dry eye" refers to a disease diagnosed as "dry eye" in accordance
with clinical diagnostic criteria, and is defined as "a multifactor disease of a lachrymal
fluid and ocular surface due to various factors, associated with ocular discomfort,
abnormality in the visual function, instability in the tear film, or disorder on the
ocular surface". Dry eye is typically diagnosed by observing that BUT from fluorescein
staining is 5 seconds or less and the patient has a subjective symptom (ocular discomfort
or abnormality in the visual function).
[0147] As used herein, "subjective symptom" refers to a symptom that can be sensed by a
patient suffering from the disease among symptoms of the disease.
[0148] As used herein, "objective symptom" refers to a symptom that can be objectively proven
by findings from image finding/numerical values of a test result (objective finding)
or the like among symptoms of the disease.
[0149] As used herein, "ocular discomfort" refers to a symptom in which an eye is uncomfortable
or an eye constantly feels uneasy.
[0150] As used herein, "ocular discomfort associated with dryness" refers to ocular discomfort
caused by dryness such as low humidity, which does not include ocular pain.
[0151] As used herein, "aqueous deficient dry eye" refers to dry eye with reduced amount
of lachrymal fluid, developed due to destruction of lachrymal gland tissue or lachrymal
fluid drainage disorder from the lachrymal gland to the ocular surface from Sjogren's
syndrome, aging, graft-versus-host disease (GVHD), or the like.
[0152] As used herein, "inhibition" of a target refers to reduction or elimination of a
phenomenon occurring within the body due to the target of inhibition. "Antagonism"
refers to a form of "inhibition" achieved by a inhibiting action due to competition
with a molecule (ligand, substrate, etc.) that naturally interacts therewith.
[0153] As used herein, "inhibit a Vi/Vc zone" refers to reduction or elimination of nerve
excitation in the Vi/Vc zone of the medulla oblongata, i.e., signaling in response
to nociception.
[0154] As used herein, "Vi/Vc zone inhibitor" refers to an agent for blocking the Vi/Vc
zone. Examples of "Vi/Vc zone inhibitor" include any substance, agent, means, and
the like that reduces or eliminates nerve excitation in the Vi/Vc zone in comparison
to the absence of the substance, agent, or means having such an action.
[0155] As used herein, "kit" refers to a unit providing parts to be provided (e.g., therapeutic
drug or medicament, prophylactic drug or medicament, the respective ingredients thereof,
user manual, and the like) which are generally separated into two or more segments.
[0156] As used herein, "instruction" refers to a document with an explanation of the method
of use of the present disclosure for physicians or other users.
(Compound)
[0157] The present disclosure can provide a composition comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof or a method of use thereof.
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
includes an R form (
CAS. No. 920332-28-1), S form (
CAS. No. 920332-29-2), and racemate (
CAS. No. 920332-27-0), but an R form ((E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
(also referred to as compound (1) in the present disclosure)) is more preferable.
[0158] A pharmaceutically acceptable salt of the compound of the present disclosure is not
particularly limited, as long as it is a salt that is pharmaceutically acceptable.
Specific examples thereof include those with hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and other mineral acids;
formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid,
capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid,
mandelic acid, and other aliphatic monocarboxylic acids, benzoic acid, salicylic acid,
and other aromatic monocarboxylic acids, oxalic acid, malonic acid, succinic acid,
fumaric acid, maleic acid, malic acid, tartaric acid, and other aliphatic dicarboxylic
acids, citric acid and other aliphatic tricarboxylic acids, and other organic carboxylic
acids; methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, and
other aliphatic sulfonic acids, benzenesulfonic acid, p-toluenesulfonic acid, and
other aromatic sulfonic acids, and other organic sulfonic acids; acid addition salts
with an acidic amino acid such as aspartic acid or glutamic acid, or the like, salts
with metal such as alkali earth metal or alkali metal such as sodium, potassium, magnesium,
or calcium, salts with an organic base such as methylamine, ethylamine, ethanolamine,
pyridine, lysine, arginine, or ornithine, ammonium salt, and the like.
[0159] These salts can be obtained by a routine method, e.g., mixing an equivalent amount
of a group of compounds of the present disclosure with a solution comprising a desired
acid or base and the like, and filtering out a desired salt, or evaporating a solvent
to collect the salt. The compound of the present disclosure or a salt thereof can
form a solvate with a solvent such as water, ethanol, or glycerol.
[0160] (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
has an excellent Transient Receptor Potential Vanilloid 1 (denoted as "TRPV1" hereinafter;
TRPV1 is also referred to as "Vanilloid Receptor 1" (VR1)) antagonizing action.
[0161] References are made to International Publication No.
WO 2007/010383,
Japanese Patent No. 4754566,
Japanese Patent No. 6230743, and International Publication No.
WO 2018/221543 for the R form (compound (1)), S form, or racemate of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
The R form (compound (1)), S form, or racemate can be manufactured by a manufacturing
method described in said publications. The content described in said publications
is incorporated herein by reference in its entirety.
[0162] TRPV1 is a TRP channel, which is cloned as a cationic channel responding to capsaicin
from the dorsal root ganglion (DRG), has sensitivity to heat of 43°C or higher and
proton, and is studied as a primary molecule of nociception (
The Journal of Japanese Biochemical Society, Vol. 85, No. 7: 561-565). It is known that TRPV1 increases its activity and elicits hyperalgesia upon inflammation
or tissue injury. For this reason, TRPV1 has drawn attention as a candidate for a
drug target that can be used for pain treatment.
[0164] The Examples of the present disclosure show that (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof can be used as a Vi/Vc zone
inhibitor. The present disclosure can provide a Vi/Vc zone inhibitor comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof. Since (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
has Vi/Vc zone inhibiting activity, the compound can be used for improvement of a
subjective symptom of dry eye, and an effect on ocular discomfort associated with
dryness in particular can be expected, as described in detail elsewhere herein.
(Dry eye)
[0165] The present disclosure can provide a composition, pharmaceutical/medicament, method,
and the like for use in preventing and/or treating dry eye. The present disclosure
shows that (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
(can be a pharmaceutically acceptable salt or solvate thereof or the like) can be
used in the treatment of dry eye. The present disclosure shows that a Vi/Vc zone inhibitor
can be used for the treatment of dry eye in another embodiment. While treatment or
prevention of dry eye treated with the composition of the present disclosure is not
particularly limited, examples thereof include improvement of a subjective symptom
or improvement of an objective symptom.
(Improvement of subjective symptom)
[0166] In one embodiment, the composition, pharmaceutical/medicament, or method of the present
disclosure can be for improvement of a subjective symptom of dry eye. In another embodiment,
the composition, pharmaceutical/medicament, or method of the present disclosure can
be for improvement of dry eye accompanied by a subjective symptom. The composition
of the present disclosure can improve ocular discomfort, dryness, visual function,
eye strain, foreign body sensation, photophobia, or blurred vision, which is not particularly
limited thereto, by improving a subjective symptom. The composition of the present
disclosure preferably improves ocular discomfort or dryness, and more preferably improves
ocular discomfort from the viewpoint of more effectively suppressing weak stimulation.
(Ocular discomfort)
[0167] In one embodiment, the composition of the present disclosure can suppress ocular
discomfort. Ocular discomfort suppressed by the composition of the present disclosure
can be caused by dryness, inflammation, instability of tear film, or the like, but
the cause is not particularly limited thereto. The composition of the present disclosure
preferably suppresses ocular discomfort associated with dryness from the viewpoint
of having a better therapeutic effect.
(Improvement of objective symptom)
[0168] In one embodiment, the composition, pharmaceutical/medicament, or method of the present
disclosure can be for improvement of an objective symptom of dry eye. In another embodiment,
the composition, pharmaceutical/medicament, or method of the present disclosure can
be for improvement of dry eye accompanied by an objective symptom. Improvement of
an objective symptom of dry eye can include change or improvement in the value of
a Schirmer's test, fluorescein staining test, tear break up time (BUT) test, number
of blinks, or the like. The composition of the present disclosure can improve superficial
punctate keratitis (SPK), tear break up time (BUT), tear secretion, hyperaemia, or
keratoconjunctival epithelial disorder, which is not particularly limited thereto,
by improving an objective symptom. The composition of the present disclosure preferably
improves superficial punctate keratitis (SPK) from the viewpoint of having a better
therapeutic effect.
(Improvement of subjective symptom and objective symptom)
[0169] In a preferred embodiment, the composition, pharmaceutical/medicament, or method
of the present disclosure can be for improvement of both a subjective symptom and
an objective symptom of dry eye. In another preferred embodiment, the composition,
pharmaceutical/medicament, or method of the present disclosure can be for improvement
of dry eye accompanied by both a subjective symptom and an objective symptom. A subjective
symptom and an objective symptom can be any subjective symptom and objective symptom
described elsewhere herein. Although not wishing to be bound by any theory, the composition
of the present disclosure, in a preferred embodiment, can be advantageous in that
a subjective symptom and an objective symptom can be improved, treated, or suppressed
at once.
(Corneal epithelial disorder)
[0170] In another aspect, the composition of the present disclosure can treat a corneal
epithelial disorder. A corneal epithelial disorder treated with the composition of
the present disclosure is a disease involving damage (i.e., wound or defect) of a
corneal epithelial cell. Examples thereof include, but are not particularly limited
to, corneal epithelial disorders due to an endogenous disease such as a decrease in
lachrymal fluid, Sjogren's syndrome, Stevens-Johnson syndrome, or xerophthalmia (dry
eye), or a postoperative, drug-induced, lesion-induced, or contact lens use-induced
exogenous disease and the like. The composition of the present disclosure can also
promote corneal wound healing.
(Types of dry eye)
[0171] While several classification methods of dry eye have been proposed, dry eye is primarily
classified as "aqueous deficient type", "increased evaporative type", and "short BUT
type". Aqueous deficient dry eye is dry eye developed due to destruction of lachrymal
gland tissue or lachrymal fluid drainage disorder from the lachrymal gland to the
ocular surface from Sjogren's syndrome, aging, graft-versus-host disease (GVHD), or
the like. A severe corneal epithelial disorder is often developed in patients with
severe aqueous deficient dry eye ("
Yomeba Wakaru! Wakareba Kawaru! Doraiai Shinryo [Understand from reading! Change from
understanding! Dry eye diagnosis and treatment], Publisher: MEDICAL VIEW CO., LTD.,
published on October 1, 2017, pages 46-58" and "
Senmonkai no Tameno Ganka Shinryo Kuorifai 19 Doraiai Supesharisuto heno Michi [Qualification
for ophthalmic diagnosis and treatment for specialists 19 Road to dry eye specialist],
Publisher: Nakayama Shoten Co., Ltd, published on November 5, 2013, pages 103-106"). Meanwhile, increased evaporative dry eye is dry eye with a normal tear secretion
function, but is developed by excessive loss of moisture from the ocular surface exposed
by decreased blinking or the like due to meibomian gland dysfunction, incomplete eyelid
closure such as lagophthalmos, operation of VDT (Visual Display Terminals), or the
like. Short BUT dry eye is dry eye with a short BUT and a subjective symptom of dry
eye, but tear secretion and keratoconjunctival epithelium are mostly normal. (
Revised Definition and Diagnostic Criteria of Dry Eye (2016), and
Journal of the Eye, Publisher: Medical-Aoi Publications, March 2017 Edition, pages
309-313"). Dry eye that can be treated or prevented by the composition of the present disclosure
includes, but is not particularly limited to, aqueous deficient dry eye, increased
evaporative dry eye, and short BUT dry eye. From the viewpoint of having a better
therapeutic effect, the composition of the present disclosure preferably treats aqueous
deficient dry eye.
(Blocking of Vi/Vc zone)
[0172] When an eye is forcibly dried in a normal animal, a nerve excitation marker, i.e.,
c-Fos positive cell count, is increased in the Vi/Vc zone of the medulla oblongata.
Thus, it is understood that a nerve through the Vi/Vc zone is involved in ocular discomfort
associated with dryness (
The Journal of Neuroscience, April 28, 2004/24 (17): 4224-4232). The c-Fos positive cell count in the Vi/Vc zone of the medulla oblongata is also
increased in an exorbital lacrimal gland extracted rat dry eye model, which is an
aqueous deficient dry eye model (
Neuroscience. 2015. 290. 204-213). Thus, a nerve through the Vi/Vc zone is involved in ocular discomfort associated
with dryness in a subjective symptom of aqueous deficient dry eye.
[0173] Spinal trigeminal nucleus are classified into subnucleus oralis (Vo), subnucleus
interpolaris (Vi), and subnucleus caudalis (Vc) and relay nociceptive or non-nociceptive
signaling for pain, tactile sensation, or the like from the oral cavity and face region.
Stimulation in a cornea is transmitted primarily through a pathway in the Vc/c1 region
or Vi/Vc zone (
J Neurophysiol. 1997 Jan; 77(1): 43-56.). The region that reacts varies depending on the type of stimulation. It is known
that the Vc/c1 region reacts to nociceptive stimulation such as heat or capsaicin,
i.e., strong stimulation (
Headache. 2012 February; 52(2): 262-273 and "
Sansashinkeiryoiki heno Kapusaishin Shigeki ni yoru Shingaijuyo ni taisuru Esutorojen
no Eikyo [Effect of estrogen on nociception from capsaicin stimulation to the trigeminal
nerve region]", Kazuaki Yamagata, Osaka University thesis), while the Vi/Vc zone reacts to weak stimulation such as dryness (
The Journal of Neuroscience, April 28, 2004·24 (17): 4224-4232).
[0174] Most currently approved eye drops that are approved as a prescription eye drop for
dry eye improve objective symptoms. An eye drop that directly treats subjective symptoms
in addition to objective symptoms does not exist, as far as the applicant is aware.
For this reason, a dry eye treating eye drop that improves both objective symptoms
and subjective symptoms is extremely desirable.
[0175] The composition of the present disclosure can be characterized in that the composition
is administered to a patient who has a subjective symptom of ocular discomfort and
has been diagnosed as having dry eye. The composition of the present disclosure can
be characterized in that the composition is administered to a patient who has an objective
symptom of superficial punctate keratitis (SPK) and has been diagnosed as having dry
eye.
(Vi/Vc zone inhibitor)
[0176] One aspect of the present disclosure can provide a Vi/Vc zone inhibitor. The Vi/Vc
zone inhibitor of the present disclosure can change signaling in response to nociception
in the Vi/Vc zone. For example, after nociception, the c-Fos expressing cell count
in the Vi/Vc zone can be reduced. In a behavioral experiment related to memory or
anxiety, elevated c-Fos expression was observed after about 30 minutes at the mRNA
level and after 1 to 2 hours at the protein level in neurons reacting to stimulation.
c-Fos is used as an indicator of activity of neurons.
[0177] Examples of Vi/Vc zone inhibitors include a substance that suppresses excitation
of the Vi/Vc zone and a substance that suppresses the function of the Vi/Vc zone.
Meanwhile, Vi/Vc zone inhibitors also include combinations of a plurality of substances
that materialize blocking of excitation of the Vi/Vc zone and the like. A Vi/Vc zone
inhibitor can be a Vi/Vc zone inhibiting compound in the present disclosure. Representative
examples of Vi/Vc zone inhibiting compounds include, but are not limited to, the compounds
described in (Vi/Vc zone blocking compound) provided in the present disclosure (e.g.,
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
and compound (1), pharmaceutically acceptable salt or solvate thereof, and the like).
Examples of substances that can be used as a Vi/Vc zone inhibitor also include other
biomolecules with an identified function such as antibodies and nucleic acids and
the like.
[0178] Other examples of Vi/Vc zone inhibitors include means for genetic modification to
suppress excitation or function of a Vi/Vc zone, cells having activity to suppress
excitation or function of a Vi/Vc zone, and the like. The Vi/Vc zone inhibitor of
the present disclosure can also be effective for a disease, condition, or the like
for which a modulation of a Vi/Vc zone is useful.
[0179] Examples of substances that suppress excitation of the Vi/Vc zone and substances
that suppress the function of the Vi/Vc zone include low molecular compounds, high
molecular compounds, nucleic acids, and antibodies that suppress excitation of a Vi/Vc
zone, low molecular compounds, high molecular compounds, nucleic acids, and antibodies
that suppress a function of a Vi/Vc zone, and the like.
(Vi/Vc zone inhibiting compound)
[0180] An embodiment of the present disclosure provides a compound that can be used as a
Vi/Vc zone inhibitor. Examples of compounds that can be used as a Vi/Vc zone inhibitor
include the (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
and compound (1) described herein, and pharmaceutically acceptable salts and solvates
thereof.
[0181] A pharmaceutically acceptable salt of a compound that can be used as a Vi/Vc zone
inhibitor is not particularly limited, as long as it is a salt that is pharmaceutically
acceptable. Specific examples thereof include those with hydrochloric acid, hydrobromic
acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and other mineral
acids; formic acid, acetic acid, propionic acid, butyric acid, valeric acid, enanthic
acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic
acid, mandelic acid, and other aliphatic monocarboxylic acids, benzoic acid, salicylic
acid, and other aromatic monocarboxylic acids, oxalic acid, malonic acid, succinic
acid, fumaric acid, maleic acid, malic acid, tartaric acid, and other aliphatic dicarboxylic
acids, citric acid and other aliphatic tricarboxylic acids, and other organic carboxylic
acids; methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, and
other aliphatic sulfonic acids, benzenesulfonic acid, p-toluenesulfonic acid, and
other aromatic sulfonic acids, and other organic sulfonic acids; acid addition salts
with an acidic amino acid such as aspartic acid or glutamic acid, or the like, salts
with metal such as alkali earth metal or alkali metal such as sodium, potassium, magnesium,
or calcium, salts with an organic base such as methylamine, ethylamine, ethanolamine,
pyridine, lysine, arginine, or ornithine, ammonium salt, and the like.
(Use of Vi/Vc zone inhibitor)
[0182] One aspect of the present disclosure can provide a composition for use in preventing
or treating dry eye, comprising a Vi/Vc zone inhibitor or a pharmaceutical/medicament
or method using the same. A composition comprising a Vi/Vc zone inhibitor or a pharmaceutical/medicament
or method using the same can be for improvement of a subjective symptom of dry eye
such as suppression of ocular discomfort associated with dryness. A composition comprising
a Vi/Vc zone inhibitor or a method using the same can also be for improvement of dry
eye. A composition comprising a Vi/Vc zone inhibitor can be an eye drop. A composition
comprising a Vi/Vc zone inhibitor can be a suspension. Aqueous deficient dry eye can
be targeted for treatment as dry eye. A composition comprising a Vi/Vc zone inhibitor
can be characterized in that the composition is administered to a patient who has
a subjective symptom of ocular discomfort and has been diagnosed as having dry eye.
The present disclosure can provide a composition for suppressing ocular discomfort
associated with dryness, comprising a Vi/Vc zone inhibitor. The present disclosure
can also provide a composition for improving a subjective symptom of dry eye, comprising
a Vi/Vc zone inhibitor.
[0183] Another aspect can provide a composition for suppressing or improving ocular discomfort
associated with dryness, comprising a Vi/Vc zone inhibitor or a pharmaceutical/medicament
or method using the same. In this application, the target patient does not need to
have been diagnosed as having dry eye. The present disclosure found that ocular discomfort
can be suppressed or improved by modulating a Vi/Vc zone, resulting in providing such
an application.
[0184] It is understood that a subjective symptom (e.g., ocular discomfort associated with
dryness) of dry eye, especially aqueous deficient dry eye, is sensed particularly
through the Vi/Vc zone, so that such a symptom can be improved with a Vi/Vc zone inhibitor.
In addition, the Examples herein show that a Vi/Vc zone inhibitor can provide an improvement
of an objective symptom of dry eye (e.g., SPK (superficial punctate keratitis)).
(Dosage form)
[0185] The composition of the present disclosure can be formulated into a suitable dosage
form. For example, the composition of the present disclosure, when used as an ophthalmic
composition, can be provided as an ophthalmic injection, ophthalmic ointment, eye
drops, or ophthalmic perfusate. The composition can be formulated into any dosage
form such as aerosol, liquid agent, extract, elixir, capsule, granule, pill, ointment,
powder, tablet, solution, suspension, or emulsion.
[0186] For example, an ophthalmic composition can be provided in a form of a suspension
prepared by suspending an active ingredient into an aqueous solvent (e.g., phosphate
buffered saline) or in a form of a liquid agent prepared by dissolving an active ingredient
into an aqueous solvent (e.g., phosphate buffered saline). The composition of the
present disclosure can be an eye drop. The composition of the present disclosure can
be a suspension.
[0187] The composition of the present disclosure can be administered through any suitable
route determined by those skilled in the art. The composition can be formulated to
be suitable for administration through a route of administration selected from, but
is not limited to, ocular injection, topical application (including application to
an eye), eye drop, intravenous injection, intravenous drip, oral administration, parenteral
administration, transdermal administration, and the like.
(Additive and/or excipient)
[0188] The composition can comprise any pharmaceutically acceptable additive and/or excipient
that is known in the art. Examples of additives include, but are not limited to, stabilizers,
pH modifiers, buffer, preservatives, and surfactants.
[0189] Examples of stabilizers include sodium hydrogen sulfite and the like. The amount
thereof is preferably 0 to about 1 w/v % with respect to the entire amount of the
composition.
[0190] Examples of pH modifiers include acids such as carbonic acid, acetic acid, and citric
acid, as well as alkali metal hydroxides such as potassium hydroxide, alkali metal
carbonates or bicarbonates such as sodium carbonate, alkali metal acetate such as
sodium acetate, alkali metal citrate such as sodium citrate, other bases, and the
like. The amount thereof is preferably 0 to 20 w/v % with respect to the entire amount
of the composition.
[0191] Examples of preservatives include sorbic acid, potassium sorbate, paraoxybenzoate
esters such as methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate,
and butyl paraoxybenzoate, quaternary ammonium salts such as chlorhexidine gluconate,
benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride, alkylpolyaminoethylglycine,
chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine, and the like.
The amount thereof can be appropriately changed depending on the type, but is, for
example, 0 to about 0.2 w/v % with respect to the entire amount of the composition.
[0192] Examples of surfactants include, but are not particularly limited to, non-ionic surfactants,
anionic surfactants, cationic surfactants, and the like. A surfactant is preferably
a non-ionic surfactant from the viewpoint of being less toxic.
[0193] Examples of non-ionic surfactants include, but are not particularly limited to, polyoxyethylene
(40) monostearate (polyoxyl 40 stearate), sorbitan sesquioleate, polyoxyethylene (20)
sorbitan monooleate (polysorbate 80), and the like.
[0194] Examples of anionic surfactants include, but are not particularly limited to, alkylbenzene
sulfonate, alkyl sulfate, alkyl polyoxyethylene sulfates, aliphatic α-sulfomethyl
ester, α-olefin sulfonic acid, and the like.
[0195] Examples of cationic surfactants include, but are not particularly limited to, benzalkonium
chloride, benzethonium chloride, and the like.
[0196] Examples of surfactant content include, but are not particularly limited to, 0 to
about 1.0 w/v % with respect to the entire amount of composition.
[0197] Eye drops can be prepared, for example, by dissolving or suspending the desired component
described above in an aqueous solvent such as sterile purified water, saline, or buffer
(e.g., phosphate buffer, citric acid buffer, acetic acid buffer, etc.) or a non-aqueous
solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or
peanut oil, adjusting the osmotic pressure to a predetermined osmotic pressure, and
applying sterilization such as mechanical sterilization. When a suspension is prepared,
a surfactant can be included therein.
[0198] An ophthalmic ointment can comprise an ointment base in addition to the various components
described above upon preparation. Examples of the ointment base include, but are not
particularly limited to, oily bases such as petroleum jelly, liquid paraffin, and
polyethylene, water soluble bases such as emulsion bases prepared from emulsifying
an oil phase and an aqueous phase with a surfactant or the like, and the like.
[0199] The composition, therapeutic agent, or prophylactic agent of the present disclosure
can be provided as a kit. In a specific embodiment, the present disclosure provides
a drug pack or kit comprising one or more containers filled with one or more components
of the composition or drug of the present disclosure. Optionally, information indicating
approval for manufacture, use, or sale for human administration by a government agency
regulating the manufacture, use, or sale of drugs/medicaments or biological products
can be displayed on such containers in a form specified by the government agency.
(Kit)
[0200] As used herein, "kit" is used when providing a composition, which should not be provided
in a mixed state for stability or the like and is preferably used by mixing immediately
prior to use, but the kit is not particularly limited thereto. Such a kit advantageously
comprises an instruction or user manual describing how the provided parts (e.g., therapeutic
drug or prophylactic drug) are used or how the reagents should be processed. When
a kit is used herein as a reagent kit, the kit generally comprises an instruction
or the like describing the method of use of the therapeutic agent, prophylactic agent,
or the like.
(Instruction)
[0201] As used herein, "instruction" provides, for example, description for the method of
detection of the present disclosure, how to use a diagnostic drug, or instruction
for administration of a drug, or the like, but the description is not limited thereto.
The instruction may have a description instructing administration to the eye as a
site of administration (e.g., by eye drop instillation, ophthalmic ointment, injection,
etc.) The instruction is prepared in accordance with a format specified by a regulatory
authority of the country in which the present disclosure is practiced (e.g., Ministry
of Health, Labour and Welfare in Japan, Food and Drug Administration (FDA) in the
U.S., or the like), with an explicit description showing approval by the regulatory authority.
An instruction is a so-called package insert or label. An instruction is generally
provided in paper media, but is not limited thereto. An instruction can also be provided
in a form such as electronic media (e.g., web sites provided on the Internet or emails)
.
(Description in the package insert)
[0202] Indication and the like (which can include characteristics of target patient or target
disease, disorder, or symptom), dosing method, dosage and administration, and precautions
can be described in instructions in a package insert (label in the US, etc.) in light
of the information based on clinical trials provided in the present disclosure.
(Route of administration)
[0203] In one embodiment, utilization methods of the present disclosure include, for example,
an eye drop, but the methods are not limited thereto. Examples thereof include modes
of administration (administration methods and dosage forms) such as ophthalmic ointment,
injection into the anterior chamber, impregnation into a sustained release agent,
subconjunctival injection, and systemic administration (oral administration and intravenous
injection).
(Dose)
[0204] The concentration of the compound of the present disclosure is not particularly limited,
but is generally about 0.1 to about 100000 µM (µmol/l). From the viewpoint of having
a better effect with less toxicity, the concentration is preferably about 0.5 to about
80000 µM. From the viewpoint of having a more significant effect, the concentration
is more preferably about 5 to about 80000 µM, still more preferably about 50 to about
75000 µM, particularly preferably about 500 to about 70000 µM, even more preferably
about 2000 to about 50000 µM, and most preferably about 5000 to about 30000 µM. Examples
of other concentration ranges generally include, but are not limited to, about 0.1
to about 1 µM, about 1 to about 10 µM, about 10 to about 100 µM, about 100 to about
1000 µM, about 1000 to about 2000 µM, about 2000 to about 4000 µM, about 4000 to about
7000 µM, about 7000 to about 10000 µM, about 10000 to about 12000 µM, about 12000
to about 15000 µM, about 15000 to about 20000 µM, about 20000 to about 22000 µM, about
22000 to about 25000 µM, about 25000 to about 30000 µM, about 30000 to about 40000
µM, about 40000 to about 50000 µM, about 50000 to about 70000 µM, about 70000 to about
85000 µM, and about 85000 to about 100000 µM. The concentration range can be determined
by appropriately combining these upper limits and lower limits.
[0205] The concentration of the compound of the present disclosure is not particularly limited,
but is about 0.00001 to about 5.0 w/v %. From the viewpoint of having a better effect
with less toxicity, the concentration is preferably about 0.00003 to about 3.0 w/v
%. From the viewpoint of having a more significant effect, the concentration is more
preferably about 0.0003 to about 3.0 w/v%, still more preferably about 0.003 to about
2.0 w/v %, particularly preferably about 0.03 to about 1.5 w/v %, even more preferably
about 0.1 to about 1.0 w/v %, and most preferably about 0.3 to about 1.0 w/v %. The
compound of the present disclosure can be effective at a broad range of concentrations.
Other examples of concentrations of the compound of the present disclosure include
about 0.00001 to about 0.0001 w/v %, about 0.0001 to about 0.001 w/v %, about 0.001
to about 0.01 w/v %, about 0.01 to about 0.02 w/v %, about 0.02 to about 0.05 w/v
%, about 0.05 to about 0.1 w/v %, about 0.1 to about 0.2 w/v %, about 0.2 to about
0.3 w/v %, about 0.3 to about 0.4 w/v %, about 0.4 to about 0.5 w/v %, about 0.5 to
about 0.6 w/v %, about 0.6 to about 0.7 w/v %, about 0.7 to about 0.8 w/v %, about
0.8 to about 0.9 w/v %, about 0.9 to about 1 w/v %, about 1 to about 1.1 w/v %, about
1.1 to about 1.2 w/v %, about 1.2 to about 1.3 w/v %, about 1.3 to about 1.4 w/v %,
about 1.4 to about 1.5 w/v %, and the like. The concentration range can be determined
by appropriately combining these upper limits and lower limits.
[0206] Examples of the concentration of an eye drop include, but are not particularly limited
to, about 0.00001 to about 5.0 w/v %. From the viewpoint of having a better effect
with less toxicity, the concentration is preferably about 0.00003 to about 3.0 w/v
%. From the viewpoint of having a more significant effect, the concentration is more
preferably about 0.0003 to about 3.0 w/v %, still more preferably about 0.003 to about
2.0 w/v %, particularly preferably about 0.03 to about 1.5 w/v %, even more preferably
about 0.1 to about 1.0 w/v %, and most preferably about 0.3 to about 1.0 w/v %. The
compound of the present disclosure can be effective at a broad range of concentrations.
Other examples of concentrations of the compound of the present disclosure include
about 0.00001 to about 0.0001 w/v %, about 0.0001 to about 0.001 w/v %, about 0.001
to about 0.01 w/v %, about 0.01 to about 0.02 w/v %, about 0.02 to about 0.05 w/v
%, about 0.05 to about 0.1 w/v %, about 0.1 to about 0.2 w/v %, about 0.2 to about
0.3 w/v %, about 0.3 to about 0.4 w/v %, about 0.4 to about 0.5 w/v %, about 0.5 to
about 0.6 w/v %, about 0.6 to about 0.7 w/v %, about 0.7 to about 0.8 w/v %, about
0.8 to about 0.9 w/v %, about 0.9 to about 1 w/v %, about 1 to about 1.1 w/v %, about
1.1 to about 1.2 w/v %, about 1.2 to about 1.3 w/v %, about 1.3 to about 1.4 w/v %,
about 1.4 to about 1.5 w/v %, and the like. The concentration range can be determined
by appropriately combining these upper limits and lower limits.
[0207] The effective amount of the drug of the present disclosure, which is effective in
treating a specific disease, disorder, or condition, can vary depending on the property
of the disorder or condition, but can be determined with a standard clinical technology
based on the descriptions herein by those skilled in the art. Furthermore, identification
of the optimal dosage range can be optionally assisted by using an
in vitro assay. Since the precise dose to be used in a compound can vary depending on the
route of administration or severity of a disease or disorder, the dose should be determined
in accordance with the judgment of a physician or status of each patient. The dosage
is not particularly limited, but can be, for example, 0.001, 1, 5, 10, 15, 100, or
1000 mg/kg body weight per dosing or within a range of two of such values.
(Sustainability)
[0208] The sustainability of the effect upon administration of the composition of the present
disclosure is not particularly limited, but is 12 hours. From the viewpoint of attaining
a better therapeutic effect, sustainability is preferably 8 hours, and more preferably
4 hours.
(Immediacy of effect)
[0209] The immediacy of the effect upon administration of the composition of the present
disclosure is not particularly limited, but an effect is observed in 5 minutes to
2 hours. From the viewpoint of attaining a better therapeutic effect, the immediacy
of effect is preferably 10 minutes to 1 hour, more preferably 20 minutes to 50 minutes,
and still more preferably 30 minutes.
(Dosing interval)
[0210] The dosing interval is not particularly limited, but a composition can be administered
at a common dosing interval, such as 1 to 6 times a day. From the viewpoint of attaining
a better effect and improved compliance of patients, the dosing interval is preferably
2 to 5 times a day, and more preferably 2 to 4 times a day. The dosage, number of
doses, dosing interval, dosing period, and dosing method can be appropriately selected
depending on the patient's age or body weight, symptom, mode of administration, target
organ, or the like. For example, the composition of the present disclosure can be
used as an eye drop. Further, a therapeutic drug preferably comprises an active ingredient
at a therapeutically effective amount or an amount effective to exert a desired action.
The effective dose can be estimated from a dose-response curve obtained from an
in vitro or animal model test system.
[0211] In one embodiment, the present disclosure can have a description on dosage and administration,
such as "used on a patient who has a subjective symptom of ocular discomfort and has
been diagnosed as having dry eye", "used on a patient who has an objective symptom
of superficial punctate keratitis (SPK) and has been diagnosed as having dry eye",
or "used on a patient who has a keratoconjunctival epithelial disorder and has been
diagnosed as having dry eye".
(General technology)
[0212] The molecular biological methodology, biochemical methodology, and microbiological
methodology used herein are well known and conventionally used in the art, which are
described, for example, in
Sambrook J. et al. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor
and its 3rd Ed. (2001);
Ausubel, F.M. (1987). Current Protocols in Molecular Biology, Greene Pub. Associates
and Wiley-Interscience;
Ausubel, F. M. (1989). Short Protocols in Molecular Biology: A Compendium of Methods
from Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience;
Innis, M. A. (1990). PCR Protocols: A Guide to Methods and Applications, Academic
Press;
Ausubel, F. M. (1992). Short Protocols in Molecular Biology: A Compendium of Methods
from Current Protocols in Molecular Biology, Greene Pub. Associates;
Ausubel, F. M. (1995). Short Protocols in Molecular Biology: A Compendium of Methods
from Current Protocols in Molecular Biology, Greene Pub. Associates;
Innis, M. A. et al. (1995). PCR Strategies, Academic Press;
Ausubel, F. M. (1999). Short Protocols in Molecular Biology: A Compendium of Methods
from Current Protocols in Molecular Biology, Wiley, and annual updates;
Sninsky, J. J. et al. (1999). PCR Applications: Protocols for Functional Genomics,
Academic Press,
Gait, M. J. (1985). Oligonucleotide Synthesis: A Practical Approach, IRL Press;
Gait, M. J. (1990). Oligonucleotide Synthesis: A Practical Approach, IRL Press;
Eckstein, F. (1991). Oligonucleotides and Analogues: A Practical Approach, IRL Press;
Adams, R. L. et al. (1992). The Biochemistry of the Nucleic Acids, Chapman & Hall;
Shabarova, Z. et al. (1994). Advanced Organic Chemistry of Nucleic Acids, Weinheim;
Blackburn, G. M. et al. (1996). Nucleic Acids in Chemistry and Biology, Oxford University
Press;
Hermanson, G. T. (1996). Bioconjugate Techniques, Academic Press,
Bessatsu Jikken Igaku [Experimental Medicine, Supplemental Volume], "Idenshi Donyu
& Hatsugen Kaiseki Jikken Ho [Experimental Methods for Transgenesis & Expression Analysis]",
Yodosha, 1997, or the like. Relevant portions thereof (which may be the entire document) are incorporated
herein by reference.
[0213] Reference literatures such as scientific literatures, patents, and patent applications
cited herein are incorporated herein by reference to the same extent that the entirety
of each document is specifically described.
[0214] The present disclosure has been described while showing preferred embodiments to
facilitate understanding. While the present disclosure is described hereinafter based
on the Examples, the above descriptions and the following Examples are provided for
the sole purpose of exemplification, not limitation of the present disclosure. Thus,
the scope of the present disclosure is not limited to the embodiments and Examples
that are specifically described herein and is limited only by the scope of claims.
[Example]
[0215] Examples of the present disclosure are described hereinafter. Biological samples
or the like, where applicable, were handled in compliance with the standards enacted
by the Ministry of Health, Labour and Welfare, Ministry of Education, Culture, Sports,
Science and Technology, or the like and, where applicable, based on the Declaration
of Helsinki or ethical codes prepared based thereon.
(Test Example 1)
Effect of 0.3 w/v % compound (1) in a rat scopolamine-induced dry eye model
(Animal used)
[0216] Male SD rats purchased from Charles River Laboratories Japan (body weight upon arrival:
254.6 g to 281.5 g) were used. Animals were raised in a breeding facility set to a
room temperature of 23°C ± 3°C, humidity of 55% RH ± 10% RH, and 12 hour illumination
(lights turned on at 08:00 and turned off at 20:00), from after arrival to the completion
date of the test. Animals were fed a solid feed (product name: Labo MR Stock, Nosan
Corporation) by ad libitum feeding. Tap water through an animal drinking water sterilization
device was made freely available with an automatic water supplying device. The test
was conducted with an approval from an animal experiment ethics committee under the
Act on Welfare and Management of Animals (Act No. 105 of October 1, 1973; final revision:
Act No. 46 on May 30, 2014).
(Tested substance)
[0217] Compound (1) was used as the tested substance. Compound (1) suspended in a vehicle
shown in Table 1 so that the concentration would be 0.3 w/v % was used as a suspension
eye drop. A compound (1)-free vehicle eye drop consisting of only a vehicle (Table
1) was used as a control group.
[Table 1]
Component |
Content (in 100 mL of formulation) |
Vehicle |
0.3 w/v % compound (1) |
Compound (1) |
- |
0.3 g |
Polysorbate 80 |
0.1 g |
0.1 g |
Phosphate buffered saline |
Suitable amount |
Suitable amount |
Total amount |
100 mL (pH 7.15) |
100 mL (pH-) |
(Test method)
(Preparation of rat scopolamine-induced dry eye model)
[0218] Scopolamine hydrobromide trihydrate (Tokyo Chemical Industry) was dissolved into
saline (Otsuka Pharmaceutical Factory) so that the concentration would be 208.3 mg/mL
(hereinafter, SC solution). The SC solution was loaded into an osmotic pump (product
name: Alzet
® osmotic pump (model number: 2ML4), DURECT Corporation).
[0219] The hair between the left and right shoulder blades of a rat was shaved (near the
implanted osmotic pump). General anesthesia was administered through inhalation of
isoflurane (product name: Forane, Abbott Japan). The shaved part was alternatingly
disinfected with 10% isodine solution (product name: Isodine Solution
® 10%, Mundipharma) and 70% ethanol, and then the skin was incised with a cutting blade
while placing a sterilized drape on the site to be incised. An osmotic pump was implanted
after inserting tweezers into the incision and peeling off subcutaneous connective
tissue from the blood vessels to create a pocket with a size at which the osmotic
pump can be implanted. Subcutaneous connective tissue was sutured in accordance with
the width of the incision wound by using an absorbable suture (product name: Vicryl,
suture thickness: J463, Johnson & Johnson). The skin was then sutured in accordance
with the width of the incision wound using a silk suture (product name: silk blade
suture with a needle, product number: F17-30, Natsume Seisakusho). 0.05 mg/kg of buprenorphine
hydrochloride injection (product name: Lepetan
® injection 0.3 mg, Otsuka Pharmaceutical) was subcutaneously administered once to
care for post-surgery pain, and 20000 units/rat of benzylpenicillin potassium (product
name: PENICILLIN G POTASSIUM 200,000 UNITS FOR INJECTION, Meiji Seika Pharma) was
subcutaneously administered once to prevent infections, each at a site away from an
incision wound.
(Post- operative management)
[0220] After implanting the osmotic pump, 0.05 mg/kg of buprenorphine hydrochloride injection
and 20000 units/rat of benzylpenicillin potassium were each subcutaneously administered
once at a site away from the surgical site on the next day and the date after next.
(Administration)
[0221] For a total of 14 days from day 8 to day 21 after implanting the osmotic pump, a
vehicle eye drop or 0.3 w/v % compound (1) suspension eye drop was administered. 5
µL of eye drop was administered to the right eye using a micropipette, 4 times a day
with an interval of 2 hours or longer. A vehicle eye drop was administered to the
Sham group.
(Observation of superficial punctate keratitis (SPK))
[0222] 5 µL of 0.1% fluorescein sodium solution (hereinafter, FL solution) was administered
using a micropipette under general anesthesia through inhalation of isoflurane. After
administering several droplets of saline as eye drops to wash away excessive FL solution,
the cornea was observed in three separate sections of top, middle, and bottom using
a slit lamp (Topcon) and given a score of 0 to 3 points each for a total full score
of 9 points in accordance with Table 2.
[Table 2]
Point |
Determination criteria |
0 |
No punctate staining |
1 |
Sparse density of punctate staining (punctate staining is separated) |
2 |
Moderate density of punctate staining (between 1 to 3 points) |
3 |
High density of punctate staining (punctate staining is nearly adjacent) |
(Preparation of Zamboni's Fixative)
[0223] NaH
2PO
4 ·2H
2O (Nacalai Tesque Inc.), Na
2HPO
4 ·12H
2O (Wako Pure Chemical Industries, Ltd.), paraformaldehyde (Wako Pure Chemical Industries,
Ltd.), and 2,4,6,-Trinitrophenol (Picric acid, Kishida Chemical Co., Ltd.) were dissolved
in ultrapure water so that the final concentration would be 0.3%, 2.9%, 2%, and 0.1
%, respectively, to prepare Zamboni's Fixative.
(Measurement of c-Fos positive cell count)
[0224] After observing SPK after 14 days (after 22 days post-surgery) from administration
of a vehicle eye drop or 0.3 w/v % compound (1) suspension eye drop, general anesthesia
was administered by inhalation of isoflurane. After a rat was allowed to bleed to
death by perfusion of saline, Zamboni's Fixative was perfused to extract the medulla
oblongata. After sectioning the extracted medulla oblongata, the medulla oblongata
was stained by immunohistochemical staining by using an anti-c-Fos antibody (product
name: Rabbit Anti-Human c-Fos Polyclonal Antibody, sc-52, Santa Cruz Biotechnology,
Inc.). A specimen was observed under a fluorescence microscope to measure the number
of cells with high stain intensity among cells stained with an anti-c-Fos antibody
within the Vi/Vc zone.
(Results)
[0225] Figure 1 shows the effect on SPK, and Table 3 shows the effect on the c-Fos positive
cell count in the Vi/Vc zone of the medulla oblongata. 0.3 w/v % compound (1) suspension
eye drop significantly reduced the SPK score after 7 days from administration (after
15 days post-surgery) compared to a vehicle eye drop, and the effect thereof was sustained
14 days after administration (22 days post-surgery). Thus, it was demonstrated that
compound (1) improves objective symptoms.
[0226] 0.3 w/v % compound (1) suspension eye drop also reduced the c-Fos positive cell count
in the Vi/Vc zone of the medulla oblongata compared to a vehicle eye drop. Thus, it
was demonstrated that compound (1) blocks the Vi/Vc zone.
[Table 3]
|
c-Fos positive cell count (cells/section) |
Sham group |
2.2 ± 0.2 |
SCOP model |
Vehicle group |
14.7 ± 6.9 |
0.3 w/v % compound (1) |
8.8 ± 3.8 |
(Test Example 2 Dose response of compound (1) with respect to the number of blinks
under a dry environment in a rat scopolamine-induced dry eye model)
(Animal used)
[0227] Male SD rats purchased from Charles River Laboratories Japan (body weight upon arrival:
253.1 g to 273.0 g) were used. Animals were raised in a breeding facility set to a
room temperature of 23°C ± 3°C, humidity of 55% RH ± 10% RH, and 12 hour illumination
(lights turned on at 08:00 and turned off at 20:00), from after arrival to breeding
date under a low humidity environment. Animals were fed a solid feed (product name:
Labo MR Stock, Nosan Corporation) by ad libitum feeding. Tap water through an ultrafiltration
device was made freely available in a water bottle. The test was conducted with an
approval from an animal experiment ethics committee under the Act on Welfare and Management
of Animals (Act No. 105 of October 1, 1973; final revision: Act No. 46 on May 30,
2014)
(Tested substance)
[0228] Compound (1) was used as a tested substance. In the same manner as Test Example 1,
compound (1) was suspended in a buffer to prepare suspension eye drops with a concentration
of compound (1) of 0.1 w/v %, 0.3 w/v %, and 1.0 w/v %. A compound (1)-free vehicle
eye drop consisting of only a vehicle was also prepared as a control group.
(Test method)
(Preparation of a rat scopolamine-induced dry eye model)
[0229] A rat scopolamine-induced dry eye model was prepared by the same method as Test Example
1.
(Low humidity environment)
[0230] After about 2.5 hours from implanting an osmotic pump, dry air supplied from an air
compressor was sent into an experiment chamber (SJ-1500N, Natsume Seisakusho) to create
a low humidity environment (20% RH or lower).
(Administration)
[0231] 5 µL of a vehicle eye drop or 0.1 w/v %, 0.3 w/v %, or 1.0 w/v % compound (1) suspension
eye drop was administered once to the right eye using a micropipette, 0.5 hours before
measuring the number of blinks.
(Measurement of number of blinks)
[0232] After 8 days or more from starting raising the rats in a low humidity environment,
the rats were taken out from a breeding cage. The animals were placed in a cage comprised
of chain link fencing on all sides (behavior measurement environment cage) to facilitate
measurement of the number of blinks. After acclimation for 0.5 hours under a normal
environment, the behavior measurement environment cage was transferred to an experiment
chamber, and the number of blinks of the right eye of rats was measured for 5 minutes
under a low humidity environment. A test was conducted in four separate phases using
the same animals after a drug withdrawal period of 2 days or more (crossover test).
(Results)
[0233] The results are shown in Figure 2. Compound (1) reduced the number of blinks in the
range from 0.1 w/v % to 1.0 w/v %, and a significant effect was observed at 0.3 w/v
% and 1.0 w/v %. Therefore, it was demonstrated that compound (1) improves a subjective
symptom in a broad range of concentrations.
(Text Example 3 Sustainability of compound (1) with respect to the number of blinks
under dry environment in a rat scopolamine-induced dry eye model)
[0234] By using the same evaluation method as Text Example 2, the sustainability of an effect
of improving a subjective symptom was examined. The number of blinks of the right
eye was measured for 5 minutes under a lower humidity condition after 0.5 hours from
single administration of vehicle eye drop or after 0.5, 4, or 8 hours from single
administration of 1.0 w/v % compound (1) suspension eye drop.
[0235] The results are shown in Figure 3. The number of blinks after 0.5, 4, and 8 hours
from administration of 1.0 w/v % compound (1) suspension eye drop can be reduced to
less than the number of blinks after 0.5 hours from administration of a vehicle eye
drop, and the number of blinks was reduced significantly, particularly after 0.5 and
4 hours. Thus, it was demonstrated that compound (1) maintains an effect of improving
a subject symptom for a long period of time.
(Text Example 4 Long-term administration test in a rat scopolamine-induced dry eye
model)
[0236] 1.0 w/v % compound (1) suspension eye drop was administered for an extended period
using a rat scopolamine-induced dry eye model prepared by the same method as Test
Example 2. The model was treated under a low humidity environment (20% RH or less)
only when measuring the number of blinks.
[0237] After one week has passed from implanting an osmotic pump, 1.0 w/v % compound (1)
suspension eye drop and a vehicle eye drop were repeatedly administered for 8 days.
5 µL of 1.0 w/v % compound (1) suspension eye drop and vehicle eye drop was administered
to the right eye 4 times a day by using a micropipette.
[0238] An effect of improving SPK (SPK score) was evaluated by the same method as Test Example
1 on day 8 of sample administration. The number of blinks of the right eye was measured
for 5 minutes under a low humidity environment after 4 hours from the initial administration
on day 7 of administration (2 weeks post-surgery) by the same method as Text Example
2.
[0239] Figure
4 shows the effect on SPK. 1.0 w/v % compound (1) suspension eye drop significantly
reduced the SPK score compared to a vehicle eye drop.
[0240] Figure
5 shows the effect on the number of blinks under a low humidity environment. 1.0 w/v
% compound (1) suspension eye drop reduced the number of blinks compared to a vehicle
eye drop.
(Discussion)
[0241] The results in Table 3 of Test Example 1 herein demonstrate that compound (1) has
an effect of blocking the Vi/Vc zone. Figure
1 of Test Example 1 and Figures
2 and
3 of Test Examples 2 and 3 demonstrate that compound (1) has an effect of improving
an objective symptom and a subjective symptom. Thus, it was demonstrated that compound
(1) has a dry eye treating effect.
[0242] Although not certain, it is inferred that compound (1) was able to improve an objective
symptom and a subjective symptom, which is a therapeutic effect on dry eye, by having
an action to block the Vi/Vc zone. Specifically, it is inferred that dry eye can be
treated by blocking the Vi/Vc zone.
(Test Example 5: Clinical test example)
(Measured endpoints)
Primary endpoints
[0243]
Safety and tolerability of compound (1)
*Measurement of the number and severity of adverse events including an abnormal change
in clinical test results, vital signs, and physical and ophthalmic test/pharmacokinetic
(PK) profiles Cmax, tmax, AUC0-last, AUC0-∞ tlast, AUC%extrap, t1/2, MRT0-last, MRT0-∞ Vd/F, and CL/F of compound (1)
Efficacy of compound (1)
*Difference between compound (1) and placebo with respect to a change in dry eye symptoms
(visual analogue scale [VAS]) Secondary endpoints
Efficacy of compound (1)
*Change in dry eye symptom (CFS score (superior, inferior, temporal, nasal, and total),
lissamine green staining score of the conjunctiva, lid wiper epitheliopathy score,
tear breakup time (TBUT))
*Change in dry eye symptom (VAS, Ocular Surface Disease Index [OSDI®], 5-Item Dry Eye Questionnaire [DEQ-5] score)
(Protocol)
(A) Single administration
[0244] Suitable subjects are screened. Subjects are randomized to receive a single administration
of a placebo or a specific concentration of compound (1) eye drop.
[0245] Blood for PK measurement is collected at predetermined points in time before administration
and after administration. For evaluation of safety of the eye and the entire body
after administration, the measured endpoints described above are evaluated.
(B) Multiple administrations
[0246] Suitable subjects are screened. Subjects are randomized to receive administration
of a placebo or a specific concentration of compound (1) eye drop. Multiple doses
are administered over a specific period.
[0247] For evaluation of safety of the eye and the entire body after administration, the
measured endpoints described above are evaluated.
(Test Example 6: Vi/Vc modulation action)
[0248] A rat scopolamine-induced dry eye model is prepared as described in Test Example
1. For a total of 14 days from day 8 to day 21 after implanting the osmotic pump,
a vehicle eye drop or eye drop containing a test compound is administered. 5 µL of
eye drop is administered to the right eye using a micropipette, 4 times a day with
an interval of 2 hours or longer.
[0249] After 14 days from administration of a vehicle eye drop or eye drop containing a
test compound (after 22 days post-surgery), general anesthesia was administered by
inhalation of isoflurane. After a rat was allowed to bleed to death by perfusion of
saline, Zamboni's Fixative was perfused to extract the medulla oblongata. After sectioning
the extracted medulla oblongata, the medulla oblongata was stained by immunohistochemical
staining by using an anti-c-Fos antibody (product name: Rabbit Anti-Human c-Fos Polyclonal
Antibody, sc-52, Santa Cruz Biotechnology, Inc.). A specimen was observed under a
fluorescence microscope to measure the number of cells with high stain intensity among
cells stained with an anti-c-Fos antibody within the Vi/Vc zone.
[0250] The Vi/Vc zone modulation function of the test compound is checked by the same method
as Test Example 1.
(Note)
[0251] As described above, the present disclosure is exemplified by the use of its preferred
embodiments. However, it is understood that the scope of the present disclosure should
be interpreted solely based on the Claims. It is also understood that any patent,
any patent application, and any references cited herein should be incorporated herein
by reference in the same manner as the contents are specifically described herein.
The present application claims priority to
Japanese Patent Application No. 2019-184053 filed on October 4, 2019 with the Japan Patent Office. The entire content thereof is incorporated herein by
reference in the same manner as if the contents are specifically described herein.
[Industrial Applicability]
[0252] The present disclosure can be used in the field of medicine, pharmaceuticals, healthcare,
biology, biochemistry, and the like.
[0253] The present invention is now exemplarily described by reference to the following
embodiments, without being limited thereto:
Embodiments
[Embodiment 1]
[0254] A composition for use in treating dry eye, comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
[Embodiment 2]
[0255] The composition of embodiment 1, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( (7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[Embodiment 3]
[0256] The composition of embodiment 1 or 2, wherein the dry eye is accompanied by a subjective
symptom.
[Embodiment 4]
[0257] The composition of embodiment 3, wherein the dry eye is accompanied by ocular discomfort
associated with dryness.
[Embodiment 5]
[0258] The composition of embodiment 1 or 2, wherein the dry eye is accompanied by an objective
symptom.
[Embodiment 6]
[0259] The composition of embodiment 1 or 2, wherein the dry eye is accompanied by a subjective
symptom and an objective symptom.
[Embodiment 7]
[0260] The composition of any one of embodiments 1 to 6, wherein a concentration of the
(E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-((7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide,
or a pharmaceutically acceptable salt or solvate thereof is about 0.1 to about 1.0
w/v %.
[Embodiment 8]
[0261] The composition of any one of embodiments 1 to 7, which is an eye drop.
[Embodiment 9]
[0262] The composition of any one of embodiments 1 to 8, which is a suspension.
[Embodiment 10]
[0263] The composition of any one of embodiments 1 to 9, wherein the dry eye is aqueous
deficient dry eye.
[Embodiment 11]
[0264] The composition of any one of embodiments 1 to 9, characterized in that the composition
is administered to a patient who has a subjective symptom of ocular discomfort and
has been diagnosed as having dry eye.
[Embodiment 12]
[0265] A Vi/Vc zone inhibitor comprising (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
[Embodiment 13]
[0266] The Vi/Vc zone inhibitor of embodiment 12, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( (7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.
[Embodiment 14]
[0267] A suspension for use in suppressing ocular discomfort associated with dryness, comprising
about 0.3 to about 1.0 w/v % of (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
or a pharmaceutically acceptable salt or solvate thereof.
[Embodiment 15]
[0268] The suspension of embodiment 14, wherein (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide
is (E)-2-(7-trifluoromethylchroman-4-ylidene)-N-( (7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.